The present invention is directed to compositions useful in alleviating the symptons of mammalian respiratory distress syndrome (RDS). Such distress syndrome may occur in newborn infants, and especially in those born prematurely; or, in some instances it may occur in mature individuals when disease or trauma causes lung failure characterized by deficiency of lung surfactant. When such syndrome occurs, medical intervention may be initiated to aid the victim over the critical period until the body's natural surfactant mechanism can develop or revive to supply the lungs with the naturally occurring surfactant. In the interim, the compositions of this invention may be introduced into the lungs of the distressed individual to temporarily provide the surfactant necessary for proper pulmonary function.
This invention was made with government support under grant No. HL 24075 awarded by the Department of Health and Human Services. The government has certain rights in this invention.
Respiratory distress syndrome occurs in newborn infants, especially in those who are born prematurely. RDS also occurs in older children and adults. The incidence in infants is currently about 30,000 a year and in older patients about 100,000 a year in the United Stated of America alone. The per capita rate is about the same in other countries. The syndrome is manifest by lung failure and the concurrent deficiency of lung surfactant. It is the commonest cause of death in the newborn and is an important contributor of mortality in adult intensive care units.
In the past several decades a number of investigators have investigated and written of the physiology of the mammalian lung. These studies have elucidated the mechanisms involved in the transfer of gases from the airspaces in the lungs across the lining tissues to the underlying vascular system. These studies have revealed the critical role played by a liquid film which lines the lung tissue surfaces. This liquid film incorporates "surfactant" therein to facilitate the proper operation of the mammalian lung. Specifically the system operates on basic physical principles involving surface tension. That is the mechanism operates through the utilization of liquid surfaces incorporating particular molecular structures dissolved therein which result in a "skin-like" effect. This phenomenon underlies the tendency of the lung's airsacs or alveoli to expel gas at all times during the respiratory cycle. If sufficiently low surface tension forces are not maintained at the lung-tissue interface, the alveoli collapse during exhalation. Even the inspiration of air through the bronchi may be ineffective in inflating collapsed alveoli. Thus gas exchange in the pulmonary circulatory system may be inadequate in the absence of the required specialized liquid surfaces.
Establishing and maintaining low surface tension at the alveolar surfaces is accomplished by an intricate biological system associated with alveolar lung tissue. Special cells commonly known as alveolar Type II cells synthesize a complex mixture of lipids, proteins, glycerides and fatty acids. This complex molecular mixture is stored in the form of lamellar bodies within the alveolar Type II cells. By a mechanism little understood, the lamellar bodies are extruded from the alveolar Type II cells into alveolar lumen where the lamellae unwind and distribute the lipid, protein, glyceride and fatty acid molecules throughout the liquid film which bathes the entire cellular covering of the alveoli walls. These molecules are referred to by the medical community as "lung surfactant". When introduced to the alveolar surfaces and the liquid film thereon, they produce an essentially mono-molecular, all pervasive layer. The surfactant molecules effectively lower the surface tension of the film to values of 10 millinewtons/meter or less which is sufficient to maintain alveolar inflation during all phases of the respiratory cycle.
The composition of lung surfactants has been investigated and the results published in a number of papers such as Respiratory Distress Syndrome, Academic Press Inc., 1973, pages 77-98. These investigations indicate that natural lung surfactant is a complex mixture of many components, the major component of which is a lipid, dipalmitoyl phosphatidyl choline (1,2 dipalmitoyl-sn-3-glycerophosphoryl choline). Dipalmitoyl phosphatidyl choline commonly abbreviated as DPPC, occurs in lung surfactant to the extent of about 41% by weight. Mixed lecithins make up about 25% by weight; cholesterol makes up about 9 % by weight; mixed proteins about 9% by weight; phosphatidyl ethanolamine, about 5%; various glycerides and phosphatidyl serine and phosphatidyl glycerol, about 4%, respectively; lysolecithin, about 2%; with sphingomyelin and fatty acids, each making up about 1%. The above noted materials and percentages are for surfactant removed from canine lungs; however the mix of materials and percentages generally hold true for the higher mammals. Both bovine and human lung surfactant also comprise a similar mix, with DPPC running in the same range of approximately 40% by weight.
Respiratory distress syndrome occurs when the necessary surfactant is either absent from, or seriously depleted in, the liquid lining of the alveolar spaces. This syndrome occurs frequently in the newborn; and especially in the premature newborn. In such individuals development of the alviolar Type II cells has not yet arrived at a stage sufficient to generate the necessary surfactant material. The maturation of the alverolar Type II cells normally occurs within the last several weeks of full term gestation. In some instances, however, congenital defects interfere with and/or delay maturation of alveolar Type II cells; or more commonly in the instance of premature birth, maturation has not progressed sufficiently to generate the necessary surfactant.
In other instances, interruption of the generation of surfactants may occur in the mature and/or adult individual under the impact of disease and/or trauma.
It will be apparent from what has been noted hereinbefore that lack of the surfactant brought about either by immaturity, disease, or trauma interferes with the ability of the lung to properly inflate during the respiration process. The absence or loss of lung surfactant can result in the collapse or deflation of the alveolar spaces thereby resulting in severe respiratory distress. Such distress, if not managed by medical intervention, may most usually result in death. In the past such medical intervention included measures such as supplying high levels of oxygen; positive pressure application to the lungs to provide adequate pulmonary ventilation; adequate attention to the maintenance of nutrition, fluid balance, blood volume, blood pressure etc. In addition, in the case of a premature newborn, it has been determined that introduction of corticosteroids induces rapid maturation of the natural surfactant production system. Steroid therapy, however, must be undertaken before the actual birth occurs in order to be truly effective in achieving early maturation of the surfactant producing systems. Where it is anticipated that a premature birth will occur, tests can be made for inadequate level of surfactant and steroid therapy can instituted to hasten the maturation of the natural surfactant production system. In many instances, however, premature birth is not anticipated and/or tests are not undertaken to note low levels of surfactants before birth.
Soon after birth the body's own corticosteroid system begins to function whereby the necessary corticosteroids are produced internally. If the infant can be maintained for relatively short periods of time, i.e. several days, maturation of the surfactant production systems will occur. Thus sufficient surfactant will soon be released into the alveolar surfaces to produce the low surface tension necessary for the full and unassisted expensive to maintain normal respiratory function.
In the case of mature individuals where the respiratory distress syndrome occurs because of disease and/or trauma, the body's natural repair mechanisms can be expected to begin functioning if the individual can be maintained for a few days. Hopefully the natural system will then be reactivated and take over the role of production of natural surfactant, to thus maintain a normal expansion of the alveolar spaces.
In order to maintain the distressed individual, over these relatively short periods of time, attempts have been made to replace the lacking surfactant with exogenous surfactant components. Such attempts were generally not successful until Fujiwara at al. (Lancet, January 12, 1980) used cow-lung extract fortified with DPPC and phosphatidyl glycerol, two of the principal components of natural lung surfactant. The Fujiwara et al. tests with such material were quite successful.
Some shortcomings of such a substitute surfactant derived from animal lung extracts are the undefined nature of the surfactant; the possibility of contamination with microorganisms; and especially the presence of foreign proteins which may lead to antigen sensitization in individuals to whom such extracts are administered. It is therefore desirable to develop a lung surfactant substitute whose composition is completely defined; wherein production may be controlled to essentially exclude any possibility of microbial contamination; and in which antigenic proteins are completely absent.
With regard to the preparation of artificial lung surfactant compositions which are free of protein, Metcalfe et al. reported (J. Applied Physiology Respiratory Environment Exercise Physiology 49, 1980) that a composition of 17 % DPPC, 20% egg phosphatidylcholine, 10% phosphatidyl inositol, and 1% palmitic acid exhibited acceptable properties. Similarly C.J. Morley at the 16th International Congress of Pediatrics held in Barcelona, Spain, September, 1980 reported that an artificial surfactant consisting of DPPC and unsaturated phosphatidyl glycerol showed promise.
The present inventor has shown in U.S. Pat. No. 4,312,860 issued Jan. 26, 1982 that a mixture of DPPC and a fatty alcohol, such as hexadecanol, effectively operates as a synthetic lung surfactant.
While the compositions referenced in the above-noted patent are useful lung surfactants and are acceptable from a medical standpoint, they do tend to aggregate and settle out during storage; and they must be carefully reconstituted if they have been stored in order to fully disperse the surfactant. It is necessary to resort to the use of organic solvents or sonication when the compositions are diluted immediately prior to use. The patented compositions should also be stored at low temperatures to prevent their deterioration before use. Thus it would be desirable to provide improved artificial lung surfactant compositions which can be easily stored and readily reconstituted for use. The present invention solves these problems.